Azalicyclooctane derivatives as anti-arrhythmic agents

ABSTRACT

A compound of formula (I) or a salt thereof, or a solvate thereof: ##STR1## wherein B represents a C 1-4  n-alkylene group wherein each carbon is optionally substituted by a C 1-6  alkyl group; Z represents a bond, CH 2 , (CH 2 ) 2  or X--CH 2  --CH 2  wherein X represents O or S; D represents CO, SO 2 , NH--CO or NH--SO 2  ; T represents a bond and U represents CH 2  or T represents CH 2  and U represents a bond; Q represents aryl, aralkyl, aralkenyl or aralkynyl, wherein the aryl moiety may be unsubstituted or substituted with 1 to 5 substituents selected from the list consisting of nitre, halogen, alkylsulfonamido, acylamido, 1H-imidazolyl, alkyl or haloalkyl, or Q represents substituted or unsubstituted: furanyl, pyranyl, thienyl, thiazolyI, imidazolyl, triazolyl or the benzo fused equivalents or furanyl, pyranyl, thienyl, thiazolyl, 1H-imidazolyl, or triazolyl, indolyl, oxoindolyl, indenyl, isoindenyl, indazolyl, indolizinyl or pyridinyl or cycloalkyl optionally fused to an aryl group; R 1 , R 2 , and R 3  each independently represents H, alkyl, OH or alkoxy or, if attached to adjacent carbon atoms, any two of R 1 , R 2 , and R 3  together with the carbon atoms to which they are attached may form a fused heterocyclic ring of five or six atoms wherein one, two or three of the said atoms are oxygen or nitrogen; Ar represents substituted or unsubstituted aryl, wherein the optional substituents are the above defined R 1 , R 2 , and R 3  or Ar represents a substituted or unsubstituted heteroaryl group; a process for the preparation of such a compound and the use of such a compound in medicine.

This application is the national phase of PCT/EP 94/02299, filed on Jul.11, 1994.

The invention relates to certain novel compounds, to pharmaceuticalcompositions containing such compounds, to a process for the preparationof such compounds and to the use of such compounds as active therapeuticagents, particularly in the treatment of atrial or ventricular cardiacarrhythmias.

European Patent Application Number 0416521 discloses certainN-benzyltropaneamides which are stated to have activity as Class IIIantiarrhythmic agents, acting by prolonging cardiac action potentialduration.

Chemical Abstracts 117:778 discloses 4-chloro-N-(4-methoxyphenyl-N-9-(2-phenylethyl)-9-azabicyclo 3.3.1!non-3-yl and related anaestheticcompounds.

The Journal of Heterocyclic Chemistry (1978), 15, 273-280 disclosesN-substituted 5- and 6-propanilido-2-Azabicyclo 2.2.2!octanes which arestated to analgesics.

The Journal of Heterocyclic Chemistry 31, 313-318, 1994 discloses aseries of N-phenylethyl-8-β-amidocamphidines and the use of suchcompounds to study the influence of certain stereochemical factors onanalgesia in this class of compounds.

The Journal of Medicinal Chemistry 1993, Vol. 36, No. 23, 3707-3720,discloses certain 9-azabicyclo 3.3.1!nonan-3β-yl benzamides and theiraffinity for dopamine D₂, dopamine D₃, serotonin 5-HT₃ and α₂ adrenergicreceptors.

Anti-arrhythmic agents are classified according to theirelectrophysiological effects on the cardiac cell (Vaugham-Williams,1970, 1989): class I agents block the fast sodium cent, class II agentsare beta-adrenergic blockers, class III agents block potassium currents,class IV agents block the calcium current, and class V agents arespecific sinus node inhibitors.

A majority of ventricular and atrial arrhythmias are related toreentrant circuit. The prolongation of myocardial refractoriness withinor surrounding such a reentrant circuit is a potential mechanism for themanagement of cardiac arrhythmias.

Because class III antiarrhythmic agents block cardiac potassiumcurrents, they prolong the repolarisation process and increaserefractoriness. Consequently class III agents represent the mostspecific class to treat reentrant arrhythmias.

However, due to their mechanism of action, i.e. a concentrationdependent increase in the cardiac action potential duration, higherdoses of class III antiarrhythmic agents may trigger arrhythmias. Sucharrhythmias, called Torsade de Pointe represent the main adverse effectfor all pure class III compounds currently in development.

It has been discovered that certain novel substituted azabicyclooctanederivatives induce a self-limiting increase of the cardiac actionpotential duration, related to a dual blockade of cardiac potassium andcalcium channels. Consequently, they have an improved pharmacologicalprofile over pure class III anti-arrhythmic agents, in particular theyare indicated to have a low proarrhythmic potential and to restore thecontractile function of the ischaemic myocardium.

Accordingly, the present invention provides a compound of formula (I):##STR2## or a salt thereof, or a solvate thereof, wherein B represents aC₁₋₄ n-alkylene group wherein each carbon is optionally substituted by aC₁₋₆ alkyl group;

Z represents a bond, CH₂, (CH₂)₂ or X--CH₂ --CH₂ wherein X represents Oor S;

T represents a bond and U represents CH₂ or T represents CH₂ and Urepresents a bond;

D represents CO, SO₂, NH--CO or NH--SO₂ ;

Q represents aryl, aralkyl, aralkenyl or aralkynyl, wherein the arylmoiety may be unsubstituted or substituted with 1 to 5 substituentsselected from the list consisting of nitro, halogen, alkylsulfonamido,acylamido, 1H-imidazoyl, alkyl or haloalkyl, or Q represents substitutedor unsubstituted: furanyl, pyranyl, thienyl, thiazolyl, imidazolyl,triazolyl or the benzo fused equivalents of furanyl, pyranyl, thienyl,thiazolyl, 1H-imidazolyl or triazolyl, indolyl, oxoindolyl, indenyl,isoindenyl, indazolyl, indolizinyl or pyridinyl or cycloalkyl optionallyfused to an aryl group;

R₁, R₂ and R₃ each independently represents H, alkyl, OH or alkoxy or,if attached to adjacent carbon atoms, any two of R₁, R₂ or R₃ togetherwith the carbon atoms to which they are attached may form a fusedheterocyclic ring of five or six atoms wherein one, two or three of thesaid atoms are oxygen or nitrogen;

Ar represents substituted or unsubstituted aryl, wherein the optionalsubstituents are the above defined R₁, R₂ and R₃ or Ar represents asubstituted or unsubstituted heteroaryl group..

Suitably, B represents CH₂ CH₂

Suitably, Z represents a bond.

Suitably, T represents a bond and U represents CH₂.

Suitably, T represents CH₂ and U represents a bond.

Suitably, D represents CO.

Suitably, Q is phenyl, favourably substituted phenyl.

An example of a substituent for Q is a nitro group.

Suitably, one or two of R₁, R₂ and R₃ represents alkoxy, for examplemethoxy, the remaining member(s) being H.

As used herein, the term "alkyl" includes straight or branched chainalkyl groups having from 1 to 12, favourably 1 to 6, carbon atoms andshall include such alkyl groups when forming part of other groups suchas alkoxy or arylalkyl groups.

As used herein, the term "alkenyl" includes straight or branched chainalkylene groups having from 2 to 12, favourably 2 to 6, carbon atoms andone or more double bonds.

As used herein, the term "alkynyl" includes straight or branched chainalkylene groups having from 2 to 12, favourably 2 to 6, carbon atoms andone or more triple bonds.

As used herein the term "aryl" includes phenyl and naphthyl, preferablyphenyl, optionally substituted with up to five, preferably up to three,groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl,hydroxyalkyl, hydroxy, amino, nitro, cyano, carboxy, alkoxycarbonyl,alkoxycarbonylalkyl, alkylcarbonyloxy or alkylcarbonyl groups.

Suitable heteroaryl groups include indole, benzofuran and benzothiophenegroups, substituted as described herein with regard to the aryl group.

As used herein, the term "cycloalkyl" includes cyclic alkylcarbon-carbon linkages of four to seven carbon atoms.

As used herein "halogen" includes fluorine, chlorine or bromine.

As used herein, the term "alkylsulfonamido" includes a radical of theformula ##STR3## wherein R^(X) is an alkyl group.

As used herein, the term "cardiac arrhythmia" relates to any variationfrom the normal rhythm of heart beat, including, without limitation,sinus arrhythmia, premature heartbeat, heartblock, fibrillation,flutter, tachycardia, paroxysmal tachycardia and premature ventricularcontractions.

The compounds of formula (I) may possess chiral carbon atoms andtherefore may exist in more than one stereoisomeric form. The inventionextends to any of the stereoisomeric forms, including enantiomers of thecompounds of formula (I) and to mixtures thereof, including racemates.The different stereoisomeric forms may be separated or resolved one fromthe other by conventional methods or any given isomer may be obtained byconventional stereospecific or asymmetric syntheses.

Suitable salts are pharmaceutically acceptable salts.

The pharmaceutically acceptable salts of the compounds of formula (I)include acid addition salts with pharmaceutically acceptable mineralacids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuricand pharmaceutically acceptable organic acids such as acetic, tartaric,maleic, citric, succinic, benzoic, ascorbic, methanesulphonic,a-keto-glutaric, a-glycerophosphoric, and glucose-1-phosphoric acids.Preferably the acid addition salt is a hydrochloride.

Pharmaceutically acceptable salts also include quaternary salts.Examples of quaternary salts include such compounds quaternised bycompounds such as R^(y) -T wherein R^(y) is C₁₋₆ alkyl, phenyl-C₁₋₆alkyl or C₅₋₇ cycloalkyl, and T is a moiety corresponding to an anion ofan acid. Suitable examples of R^(y) include methyl, ethyl and n- andiso- propyl; and benzyl and phenethyl. Suitably T includes halide suchas chloride, bromide and iodide.

Pharmaceutically acceptable salts also include pharmaceuticallyacceptable N-oxides, and the invention extends to these.

The compounds of the formula (I) and their salts may also form solvates,especially pharmaceutically acceptable solvates, such as hydrates, andthe invention extends to these, and especially to the pharmaceuticallyacceptable solvates.

The salts of the compounds of the formula (I) which are notpharmaceutically acceptable may be useful as intermediates in thepreparation of pharmaceutically acceptable salts of compounds of formula(I) or the compounds of the formula (I) themselves, and as such form anaspect of the present invention.

A compound of formula (I) or a salt thereof, or a solvate thereof, maybe prepared by reacting a compound of formula (II): ##STR4## wherein B,Z, T, U, R₁, R₂, R₃ and Ar are as defined in relation to formula (I)with a reagent of formula (III);

    QL.sup.1                                                   (III)

wherein Q is as defined in relation to formula (I) and:

(a) for compounds of formula (I) wherein D is CO or SO₂, L¹ representsCOX or SO₂ X respectively, wherein X is a leaving group such as ahalogen; and

(b) for compounds of formula (I) wherein D is NH--CO, L¹ is N═C═O;

(c) for compounds of formula (I) wherein D is NH--SO₂, L¹ is NH--SO₂.N₃;

and thereafter, if required preparing a pharmaceutically acceptable saltof the compound of formula (I) and/or a pharmaceutically acceptablesolvate thereof.

The reaction conditions for the reaction between compounds of formulae(II) and (III) are conventional conditions appropriate to the nature ofthe reagent used, generally however the reaction may be carried out inan inert solvent, such as methylene chloride, at any suitabletemperature providing a convenient rate of formation of the desiredproduct, generally at an ambient to elevated temperature, convenientlyat the reflux temperature of the solvent and preferably in the presenceof a base such as triethylamine.

The compounds of formula (II) may be prepared by reducing a compound offormula (IV): ##STR5## wherein B, Z, T, U, R₁, R₂, R₃ and Ar are asdefined in relation to formula (I).

The reduction of the compound of formula (IV) may be effected using anyappropriate reduction method, for example metal hydride reduction usinga lithium hydride such as lithium aluminium hydride in an aproticsolvent such as tetrahydrofuran (THF), or with sodium cyanoborohydridein a protic solvent such as methanol in the presence of methanolic HCl,or with sodium in an alcohol such as pentanol, at any suitabletemperature which provides a convenient rate of reaction, generally atambient to an elevated temperature, conveniently at ambient temperaturefor the metal hydride reduction or at reflux for the sodium alcoholreduction.

A compound of formula (IV) may be prepared by reacting a compound offormula (V): ##STR6## wherein Z, R₁, R₂ and R₃ are as defined inrelation to formula (I), with a compound of formula (VI): ##STR7##wherein B, T, U and Ar are as defined in relation to the compound offormula (I).

The reaction between the compounds of formulae (V) and (VI) may becarried out in a solvent such as toluene, with a suitable catalyst suchas p-toluenesulfonic acid, at any suitable temperature providing aconvenient rate of formation of the desired product, generally at anelevated temperature and conveniently at the reflux temperature of thesolvent; or in methanol at ambient temperature; the water produced inthe reaction may be removed by any conventional means, for example bymeans of a Dean and Stark apparatus.

The ketones of formula (VI) wherein T is CH₂ and U is a bond, are knowncompounds or they may be obtained by procedures analogous to those usedto prepare known compounds, for example by means of a Robinson-Schopfcyclisation following the general procedure described by P. Doster, T.Himbert, M. Langlois, B. Bucher and G. Mocquet in Eur. J. Meal. Chem.1984, 19, 105-110 and summarized in Scheme 1: ##STR8## The ketones offormula (VI) wherein T is bond and U is CH₂, may be prepared by reactinga compound of formula (VII): ##STR9## wherein B and Ar are as defined inrelation to the compound of formula (I) and W is an alkylene chain,conveniently 2,2-dimethylpropyl, in acidic medium for example aqueousHCl, at any suitable temperature providing a convenient rate offormation of the desired product, generally at an ambient to elevatedtemperature, conveniently at 60° C.

A compound of formula (VII) may be obtained by procedures analogous tothose used to prepare known compounds, for example those disclosed by S.J. Law et al. in J. Heterocyclic Chem. 1978, 15, 273 and summarized inScheme 2.

Scheme 2 in which Ar, B and W are as defined above: ##STR10##

The compounds of formulae (III) are known commercially availablecompounds or they may be obtained by procedures analogous to those usedto prepare known compounds, for example compounds of formula (III):wherein L¹ represents CO.X may be prepared according to methodsdescribed in Organic Syntheses Coll. Vol. I, page 394 or OrganicSyntheses Coll. Vol. III, page 29, wherein L¹ represents SO₂ X accordingto methods described in Organic Syntheses Coll. Vol. VIII, page 104 andfor compounds of formula (III) wherein L¹ represents N═C═O according tomethods described in Organic Syntheses Coll. Vol. III, page 846. Alsothe compounds of formula (III) wherein L¹ represents NH.SO₂. N₃ may beprepared according to methods described in J. Medical Chemistry, (1972),15, 538.

It will be appreciated that in any of the abovementioned reactions anyreactive group in the substrate molecule may be protected, according toconventional chemical practice.

Suitable protecting groups in any of the abovementioned reactions arethose used conventionally in the art. The methods of formation andremoval of such protecting groups are those conventional methodsappropriate to the molecule being protected.

As mentioned above the compounds of the invention are indicated ashaving useful therapeutic properties: The present invention accordinglyprovides a compound of formula (I), or a pharmaceutically acceptablesalt thereof and/or a pharmaceutically acceptable solvate thereof, foruse as an active therapeutic substance.

More particularly, the present invention provides a compound of formula(I), or a pharmaceutically acceptable salt thereof and/or apharmaceutically acceptable solvate thereof, for use in the treatment ofand/or prophylaxis of arrhythmia, especially cardiac arrhythmia such asventricular arrhythmia, and also ischeamic rhythm disorders.

A compound of formula (I), or a pharmaceutically acceptable salt thereofand/or a pharmaceutically acceptable solvate thereof, may beadministered per se or, preferably, as a pharmaceutical composition alsocomprising a pharmaceutically acceptable carrier.

Accordingly, the present invention also provides a pharmaceuticalcomposition comprising a compound of the general formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate thereof, and a pharmaceutically acceptable carrierthereof.

A compound of formula (I) or a pharmaceutically acceptable salt thereofand/or a pharmaceutically acceptable solvate thereof is normallyadministered in unit dosage form.

An amount effective to treat the disorder hereinbefore described dependsupon such factors as the efficacy of a compound of formula (I), theparticular nature of the pharmaceutically acceptable salt orpharmaceutically acceptable solvate chosen, the nature and severity ofthe disorders being treated and the weight of the mammal. However, aunit dose will normally contain 1 to 50 mg for example 2 to 15 mg, ofthe compound of the invention.

Unit doses will normally be administered once or more than once a day,for example 2, 3, 4, 5 or 6 times a day, more usually 2 to 4 times aday, such that the total daily dose is normally in the range, for a 70kg adult of 1 to 300 mg, more usually 4 to 100 mg, for example 10 to 60mg, that is in the range of approximately 0.02 to 5 mg/kg/day, moreusually 0. 1 to 2 mg/kg/day, for example 0.1 to 0.5 mg/kg/day.

In such treatment, the compound may be administered by any suitableroute, e.g. by the oral, parenteral or topical routes. For such use, thecompound will normally be employed in the form of a pharmaceuticalcomposition in association with a human or veterinary pharmaceuticalcarrier, diluent and/or excipient, although the exact form of thecomposition will naturally depend on the mode of administration.

Compositions are prepared by admixture and are suitably adapted fororal, parenteral or topical administration, and as such may be in theform of tablets, capsules, oral liquid preparations, powders, granules,lozenges, pastilles, reconstitutable powders, injectable and infusablesolutions or suspensions, suppositories and transdermal devices. Orallyadministrable compositions are preferred, in particular shaped oralcompositions, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colourants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and othersimilar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

Solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dose forms are preparedcontaining a compound of the present invention and a sterile vehicle.The compound, depending on the vehicle and the concentration, can beeither suspended or dissolved. Parenteral solutions are normallyprepared by dissolving the active compound in a vehicle and filtersterilising before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are also dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the active compound is suspended in the vehicle instead ofbeing dissolved and sterilised by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the active compound.

For topical administration, the composition may be in the form of atransdermal ointment or patch for systemic delivery of the compound andmay be prepared in a conventional manner, for example, as described inthe standard textbooks such as `Dermatological Formulations`--B. W.Barry (Drugs and the Pharmaceutical Sciences--Dekker) or HarrysCosmeticology (Leonard Hill Books).

In addition such compositions may contain further active agents such asanti-hypertensive agents and diuretics.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

As used herein the ten `pharmaceutically acceptable` embraces compounds,compositions and ingredients for both human and veterinary use: forexample the term `pharmaceutically acceptable salt` embraces aveterinarily acceptable salt.

The present invention further provides a method for the treatment and/orprophylaxis of arrhythmia, especially cardiac arrhythmia such asventricular arrhythmia, and also ischeamic rhythm disorders in a humanor non-human mammal which comprises administering an effective,non-toxic, amount of a compound of the general formula (I), or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof to a human or non-human mammal in needthereof.

Conveniently, the active ingredient may be administered as apharmaceutical composition hereinbefore defined, and this forms aparticular aspect of the present invention.

In the treatment and/or prophylaxis of arrhythmia and/or ischeamicarrhythmia disorders the compound of the general formula (I), or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof, may be taken in doses, such as thosedescribed above.

Similar dosage regimens are suitable for the treatment and/orprophylaxis of non-human mammals.

In a further aspect the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt thereof and/or apharmaceutically acceptable solvate thereof, for the manufacture of amedicament for the treatment of arrhythmia, especially cardiacarrhythmia such as ventricular arrhythmia, and also ischeamic rhythmdisorders.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure to ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of theactive compound.

For topical administration, the composition may be in the form of atransdermal ointment or patch for systemic delivery of the activecompound and may be prepared in a conventional manner, for example, asdescribed in the standard textbooks such as `DermatologicalFormulations`--B. W. Barry (Drugs and the PharmaceuticalSciences--Dekker) or Harrys Cosmeticology (Leonard Hill Books).

No toxicological effects are indicated when an active compound isadministered in the above mentioned dosage ranges.

The following Examples illustrate the invention but do not limit it inany way.

Description 1

8- 2-(3,4-Dimethoxyphenyl)ethyl!-8-aza-bicyclo 3.2.1!octan-3-one.##STR11##

Following a general procedure previously described (P. Doster et al.Eur. I. Med. Chem. 1984, 19, 105), 8.2 g (62 mmol)2,5-dimethoxytetrahydrofuran were heated at 80° C. in 75 ml of 0.1Naqueous HCl for 1 h. After cooling to 10° C., 10 g (68.4 mmol) acetonedicarboxylic acid, 12.4 g (68.5 mmol) 2-(3,4-dimethoxyphenyl)ethylamine,6.13 g (74.7 mmol) sodium acetate and 5.7 ml 12N aqueous HCl were addedwile stirring. Stirring was maintained overnight at room temperature.The aqueous mixture was neutralized and extracted with methylenechloride. The organic phase was washed with brine, dried over MgSO₄ andconcentrated. The filtrate was concentrated and the residual oil waspurified by chromatography on silica gel using ethyl acetate as eluent,affording 12 g of an oil pure by TLC.

¹ H NMR(CDCl₃) δ(ppm): 1.51-1.68 (m,2H); 1.95-2.11 (m,2H); 2.20 (broadd,J=15.2Hz,2H); 2.67 (dd,J=4.3Hz and 16.0Hz,2H); 2.82 (broad band,4H);3.52-3.64 (m,2H); 3.86 (s,3H,OCH₃); 3.88 (s,3H, OCH₃); 6.71-6.86 (m,3H).

Description 2

N-(3,4-Dimethoxyphenyl)-8- 2-(3,4-dimethoxyphenyl)ethyl!-8-aza-bicyclo3.2.1!octan-3-amine. ##STR12##

To a stirred solution of 4 g (26 mmol) 3,4-dimethoxyaniline and 5 ml 14Nmethanolic HCl in 200 ml methanol, were added 5.7 g (20 mmol) of 8-2-(3,4-dimethoxyphenyl)ethyl!-8-azabicyclo 3.2.1!octane-3-one (D1),followed by addition of 1 g (16 mmol) sodium cyanoborohydride. Thereaction mixture was stirred overnight, slightly acidified andconcentrated to dryness. The crude residue was filtered over a shortcolumn of silica gel using 95:5 methylene chloride:methanol. Theexpected fraction was triturated with ethyl acetate affording 4 g (47%)of the desired compound. mp.: 220° C. ¹ H NMR shows a mixture of twoconformations of the title compound.

¹ H NMR(CDCl₃) δ(ppm): 1.85-2.01 (broad d,J=14.7Hz,2H); 2.03-2.45(m,4H); 2.71-3.25 (broad m,6H); 3.70-3.90 (m, 1H) overlapped by3.61-3.76 (m,2H), 3.81 (s,3H,OCH₃), 3.83 (s,3H, OCH₃), 3.85 (s,3H,OCH₃),and 3.88 (s,3H,OCH₃); 6.10 (dd,J=2.4Hz, J'8=2Hz, 1H); 6.21 (dd,J=2.4Hz,1H); 6.75 (d,J'=8.2Hz, 1H); 6.79 (2H); 6.86 (1H).

Description 3

2- 2-(3,4-Dimethoxyphenyl)ethyl!-spiro 5',5'-dimethyl-2-azabicyclo2.2.2!octane-5,2'- 1',3'!-dioxane! ##STR13##

Following a general procedure previously described (S-J. Law et al., J.Heterocyclic Chem., 1978, 15, 273), a mixture of 11.9 g (42 mmol) ofspiro ethyl 5',5'dimethyl-2-azabicyclo 2.2.2!octane-5,2'-1',3'!-dioxane-2-carboxylate! and 11.8 g (210 mmol) of potassiumhydroxide in 120 ml of ethylene glycol was heated at 160° C. under argonfor 14 hours. The reaction mixture was cooled, diluted with 150 ml ofwater, and extracted with methylene chloride (3×100 ml). The combinedextracts were washed with water (2×50 ml), dried over MgSO₄ andevaporated to give a viscous brown oil which was dissolved in 80 ml ofacetonitrile. 6.8 g (34 mmol) of 2-(3,4-dimethoxyphenyl)-1-chloroethane,3.22 g (32 mmol) of triethylamine, and a catalytic amount of KI wereadded. The reaction mixture was refluxed for 30 h then stirred at roomtemperature for 48 h. The reaction mixture was concentrated in vacuo,diluted with methylene chloride, washed with water, dried over MgSO₄,and concentrated in vacuo. 8.8 g of a white solid pure by TLC wasisolated.

¹ H NMR (CDCl₃)δ(ppm): 0.93(s,3H); 1.01(s,3H); 1.58-1.80(m,2H);1.80-2.05(m,3H); 2.15-2.75(m,3H); 2.90-3.30(m,5H); 3.40-3.60(m,5H);3.85(s,3H); 3.88(s,3H); 6.75-6.85(m,3H).

Description 4

2- 2-(3,4-Dimethoxyphenyl)ethyl!-2-azabicyclo 2.2.2!octan-5-one##STR14##

A mixture containing 380 mg (mmol) of 2-2-(3,4-dimethoxyphenyl)ethyl!-spiro 5',5'-dimethyl-2-azabicyclo2.2.2octane-5,2'- 1',3'!-dioxane! (D3) and 6 ml of 10% aqueous HCl washeated at 60° C. for 18 h. The reaction mixture was washed withmethylene chloride (3×5ml). The aqueous solution was treated with sodiumcarbonate and extracted with methylene chloride (3×10ml). The combinedorganic extracts were dried over MgSO₄, and concentrated in vacuoleading to 250 mg of a clean product by TLC.

¹ H NMR (CDCl₃)δ(ppm): 1.55-1.70(m,1H); 1.75-2.10(m,2H);2.15-2.30(m,2H); 2.30-2.40(m, 1H); 2.60-2.85(m,5H); 2.85-3.05(m, 1H);3.05-3.20(m,2H); 3.85(s,3H); 3.87(s,3H); 6.65-6.85(m,3H).

Description 5

N-(3,4-Dimethoxyphenyl)-2- 2-(3,4-dimethoxy-phenyl)ethyl!-2-azabicyclo2.2.2!octan-5-amine ##STR15##

1.58 g (5.5 mmol) of 2- 2-(3,4-dimethoxyphenyl)ethyl!-2-azabicyclo2.2.2!octan-5-one (D4) was added to a solution of 1.10 g (7.2 mmol) of3,4-dimethoxyaniline in 30 ml of MeOH and 1.4 ml of methanolic HCl. 274mg (4.3 mmol) of sodium cyanoborohydride was then added. The reactionmixture was allowed to stir at room temperature overnight. Concentratedaqueous HCl (1.8 ml) was added and the mixture was concentrated invacuo. The residue was token up with 50 ml of water and 3 ml of 15%aqueous NaOH and extracted with methylene chloride (3×30 ml). Thecombined organic extracts were dried over MgSO₄ and concentrated invacuo, giving rise to 1.38 g of a clean product (mixture ofstereoisomers) after purification by filtration through a pad of silicagel. The stereoisomers were separated by flash chromatography on silicagel using methanol: methylene chloride (5:95) as eluent.

¹ H NMR (CDCl₃)δ(ppm) isomer I: 1.50-2.00 (m,3H); 2.00-2.45(m, 4H);2.50-2.80(m, 1H); 3.00-3.25(m,4H); 3.25-3.35(m, 1H); 3.60-3.75(m,2H);3.79(s,3H); 3.84(s,3H); 3.85(s,3H); 3.88(s,3H); 6.11 (dd,J₁ =2.5Hz,J₂=8.5Hz, 1H); 6.38(d,J=2.5Hz,1H); 6.71(d,J=8.5Hz, 1H); 6.75-6.85(m,3H).

Isomer II: 1.30-1.50(m,2H); 1.55-1.80(m,3H); 1.85-2.25(m,3H);2.75-3.60(m,7H); 3.80(s,3H); 3.84(s,3H); 3.85(s,3H); 3.88(s,3H);6.13(dd,J₁ =2.5Hz,J₂ =8.5Hz, 1H); 6.27(d,J=2.5Hz, 1H); 6.72(d,J=8.5Hz,1H); 6.75-6.90(m,3H).

EXAMPLE 1

N-(3,4-Dimethoxyphenyl)-N- 8-2-(3,4-dimethoxyphenyl)ethyl!-8-aza-bicyclo3.2.1!oct-3-yl!-4-nitrobenzamide, hydrochloride. ##STR16##

To a room temperature stirred solution of 1 g (2.3 mmol) ofN-(3,4-dimethoxyphenyl)-8- 2-(3,4-dimethoxyphenyl)ethyl!-8-aza-bicyclo3.2.1!octan-3-amine (D2) and 0.3 g (2.8 mmol) of triethylamine in 50 mlof chloroform, were added dropwise 0.5 g (2.7 mmol) of 4-nitrobenzoylchloride. Stirring was then continued at more temperature for 4 hours.The mixture was washed successively with water, diluted aqueous HCl,water, diluted aqueous NaOH, water, then dried over MgSO₄ andconcentrated. The residue was purified by chromatography on silica gelusing 95:5 methylene chloride:methanol. The desired fraction wasrecrystallised from ethyl acetate affording the free base of the titlecompound as white crystals of mp.:163° C.

¹ H NMR(CDCl₃)δ(ppm): 1.26-1.60 (m,4H); 1.86-2.10 (m,2H); 2.30-2.64(m,4H); 2.64-2.82 (m,2H); 3.23-3.50 (m,2H); 3.75 (s,3H,OCH₃); 3.81(s,3H,OCH₃); 3.85 (s,3H,OCH₃); 3.88 (s,3H,OCH₃); 4.73-5.08 (m,1H);6.34-6.94 (m,6H); 7.37 (broad d,J=8.23Hz,2H); 7.99 (broadd,J=8.23Hz,2H).

The product was then dissolved in a 1: 1 mixture of methylenechloride:ethyl acetate and 0.7 ml of 0.55M anhydrous HCl in ether wereadded. The mixture was partly concentrated, then it crystallisedaffording 230 mg of the title compound as pale yellow crystals.mp.:165°-167° C.

¹ H NMR(CDCl₃)δ(ppm): 2.13-2.61 (m,6H); 2.91-3.18 (m,4H); 3.18-3.34(m,2H); 3.65-4.00 (m,2H) overlapped by 3.79 (s,3H,OCH₃), 3.83(s,3H,OCH₃), 3.86 (s,3H,OCH₃), and 3.88 (s,3H,OCH₃); 4.91-5.20 (m,1H);6.41 (dd,1H); 6.52-6.66 (m,2H); 6.80 (broad band,2H); 6.88 (broad s,1H); 7.43 (broad d,J=8.91Hz,2H); 8.03 (broad d,J=8.91Hz,2H); 11.97(broad band,1H exchangeable with D₂ O).

Example 2

N-(3,4-Dimethoxyphenyl)-N- 2-(3,4-dimethoxyphenyl)ethyl!-2-azabicyclo2,2,2!oct-5-yl!-4-nitrobenzamide hydrochloride. ##STR17##

A mixture containing 65 mg (0.15 mmol) of N-(3,4-dimethoxyphenyl)-2-2-(3,4-dimethoxy-phenyl)ethyl!-2-azabicyclo 2.2.2!octan-5-amine (D5), 24mg (0.24 mmol) of triethylamine, and 41 mg (0.22 mmol) in 4 ml CH₂ Cl₂was stirred at room temperature for 1 h. The reaction mixture was thenwashed with brine, dried over MgSO₄, and concentrated in vacuo.Purification by flash chromatography on silica gel (methylenechloride:methanol 95:5 as eluent) afforded clean separated stereoisomers(62 mg all together) as amorphous solids. Each stereoisomer was thensubmitted to the following procedure: 250 mg of one stereoisomer (0.43mmol) was dissolved in methylene chloride and dried over MgSO₄. Afterfiltration, the solution was concentrated in vacuo. The residue wastaken up with methanol and etheral HCl. The solution was concentrated invacuo and the residue was triturated with diethyl ether and dried invacuo giving rise to 130 mg of a yellow foam. m.p. around 140° C.

¹ H NMR (CDCl₃)δ(ppm): Stereoisomer I (presence of two protomers)1.65-2.55(m,5H); 2.60-3.70(m,9H); 3.70-4.00(singlets,12H);4.55-4.80(m,1H); 6.40-6.85(m,6H); 7.45(dd,J=8.7Hz,2H); 8.04(dd,J₁=3.15Hz,J₂ =8.75Hz,2H); 12.00+12.30(two broad s, 1H exchangeable with D₂O). Stereoisomer II (presence of two protomers) 1.50-2.30(m,5H);2.40-3.55(m,8H); 3.60-4.05(m,13H); 4.75-5.05(m, 1H); 6.35-6.90(m,6H);7.38(dd,J₁ =3Hz,J₂ =8.7Hz,2H); 8.02(m,2H); 12.4(broad s, 1H exchangeablewith D₂ O).

Pharmacological Data

Methodology

Guinea pigs (300-350 g) were anesthetized by intravenous injection ofsodium pentobarbital (60 mg/kg). After thoracotomy the heart was rapidlyexcised and placed in oxygenated Tyrode solution. Papillary muscles wereremoved from the right ventricle. Preparations were then fixed to thesilastic base of a 5 ml organ bath and superfused with oxygenated Tyrodesolution maintained at 37°±1° C.

The modified Tyrode solution (pH 7.35) contained the following (mM):NaCl 125, KCl 4.0, MgCl₂ 0.5, CaCl₂ 1.8, NaHCO₃ 24, NaH₂ PO₄ 0.9 andglucose 5.5. The solution was equilibrated with a gas mixture of 95% O₂-5% CO₂.

After a stabilisation period (at least 1 h), transmembrane actionpotentials were recorded with conventional microelectrodes (10 MOhm)connected to a high input impedance amplifier (BIOLOGIC VF 180).External stimuli were delivered to the preparation with bipolar platinumelectrodes placed at one end of the muscle. The pulse duration was 1 msand the amplitude was twice threshold. The basic cycle length was 1000ms (PULSAR 6i stimulator). The signals were monitored on a storageoscilloscope (GOULD 1602) and simultaneously recorded on a digital taperecorder (BIOLOGIC DTR 1200) for further analysis.

Measurements were made on resting membrane potential (RMP), actionpotential amplitude (APA) and action potential durations at 30, 50, and90% repolarization (APD30, APD50 and APD90 respectively). Recordingswere made after 30 min of equilibration for each concentration. Onlyrecordings in which the same impalement was maintained throughout theentire experiment were used for analysis. ##STR18## Toxicology: Notoxicological effects were indicated for the compounds of the inventionin the above mentioned tests.

We claim:
 1. A compound of formula (I): ##STR19## or a salt thereof, ora solvate thereof, wherein B represents a C₁₋₄ n-alkylene group whereineach carbon is optionally substituted by a C₁₋₆ alkyl group; .Zrepresents a bond, CH₂, (CH₂)₂ or X--CH₂ --CH₂ wherein X represents O orS; D represents CO, SO₂, NH--CO or NH--SO₂ ; T represents a bond and Urepresents CH₂ or T represents CH₂ and U represents a bond; Q representsaryl, aralkyl, aralkenyl or aralkynyl, wherein the aryl moiety may beunsubstituted or substituted with 1 to 5 substituents selected from thelist consisting of nitro, halogen, alkylsulfonamido, acylamido,1H-imidazolyl, alkyl or haloalkyl, or Q represents substituted orunsubstituted: furanyl, pyranyl, thienyl, thiazolyl, imidazolyl,triazolyl or the benzo fused equivalents of furanyl, pyranyl, thienyl,thiazolyl, 1H-imidazolyl or triazolyl, indolyl, oxoindolyl, indenyl,isoindenyl, indazolyl, indolizinyl or pyridinyl or cycloalkyl optionallyfused to an aryl group; R₁, R₂ and R₃ each independently represents H,alkyl, OH or alkoxy or, if attached to adjacent carbon atoms, any two ofR₁, R₂ or R₃ together with the carbon atoms to which they are attachedmay form a fused heterocyclic ring of five or six atoms wherein one, twoor three of the said atoms are oxygen or nitrogen; Ar representssubstituted or unsubstituted aryl, wherein the optional substituents arethe above defined R ₁, R₂ and R₃.
 2. A compound according to claim 1,when B represents CH₂ CH₂.
 3. A compound according to claim 1, wherein Zrepresents a bond.
 4. A compound according to claim 1, wherein Trepresents a bond and U represents CH₂.
 5. A compound according to claim1 wherein T represents CH₂ and U represents a bond.
 6. A compoundaccording to claim 1, wherein D represents CO.
 7. A compound accordingto claim 1, wherein Q is a nitrophenyl group.
 8. A compound according toclaim 1 being:N-(3,4-dimethoxyphenyl)-N- 8-2-(3,4-dimethoxyphenyl)ethyl!-8-aza-bicyclo3.2.1!oct-3-yl!-4-nitrobenzamide; N-(3,4-dimethoxyphenyl)-N-2-(3,4-dimethoxyphenyl)ethyl!-2-azabicyclo2.2.2!oct-5-yl!-4-nitrobenzamide;or a salt thereof or a solvate thereof.9. A pharmaceutical composition comprising a compound of formula (I), asdefined in claim 1, or a pharmaceutically acceptable salt thereof and/ora pharmaceutically acceptable solvate thereof, and a pharmaceuticallyacceptable carrier.
 10. A method for the treatment and/or prophylaxis ofarrhythmia in a human or non-human mammal which comprises administeringan effective, non-toxic, amount of a compound of formula (I) as definedin claim 1, or a pharmaceutically acceptable salt thereof and/or apharmaceutically acceptable solvate thereof to a human or non-humanmammal in need thereof.